Promotion of feed efficiency in animals

ABSTRACT

Feed supplements, which increase the dwell time of ingested nutrient matter in the gastrointestinal tract of food producing animals, and which provide for increased digestion and absorption of ingested nutrient matter, are administered to food producing animals to increase feed efficiency.

This application is a continuation-in-part of application Ser. No.109,848 filed Jan. 7, 1980 now abandoned.

FIELD OF THE INVENTION

This invention relates to the field of agents used in promoting feedefficiency in animals, particularly when administered as feed additives,and to a method for promoting the growth rate of food-producing animals,especially livestock and poultry, for increasing animal products, forexample, milk production in mammalian species and egg production inavian species.

It is generally accepted that the meat, poultry dairy and cultivatedfishing industries provide the most inefficient source of food for humanconsumption. These industries use feed sources (for example, grains,fruits, and vegetables) which are also a primary source of nutrients forhumans. The production of livestock, poultry and cultivated fish entailsthe consumption of more primary source protein and carbohydrates fit forhuman consumption than is replaced by that of the resultant animal. Inaddition to the actual reduction in primary source foods for humanconsumption created by these industries, the cost of protein andcarbohydrate supplied for human consumption through secondary sources issubstantially magnified. In view of these considerations, there is needfor improvement in the utilization of animal feed in the raising ofanimals as secondary food sources.

REPORTED DEVELOPMENTS

A number of synthetic chemical compositions and naturally occurringmaterials have been utilized to increase the growth rate of animals andto decrease the consumption of animal foodstuff. These agents fall intoa number of categories, including: antibacterials, such as, sulfa drugsand antibiotics; parasitic prophylaxis; metabolic drugs; sedatives ortranquilizers; and, in ruminants, nitrogen supplements and rumenbacterial respiration modifiers.

The antibacterials are effective by reducing the incidence of bacterialdisease in the animal population.

The antiparasitic agents are effective in reducing the incidence ofparasitic infection.

Metabolic drugs increase metabolic synthesis of protein and include thehormones, such as, estrogens, progesterone and diethylstilbesterol.

Sedatives and tranquilizers effect a reduction in animal movement andhyperactivity resulting in greater protein synthesis and weightretention. Sedatives and tranquilizers of the triazole and benzdiazepineclass of compounds have been disclosed as useful in U.S. Pat. Nos.3,914,245 to Gall et al and 3,933,794 to Hester et al.

Ruminant feed containing supplemental nitrogen enhance proteinsynthesis. Nitrogen supplements have been disclosed in U.S. Pat. Nos.:3,989,846 to Helgerson (slow release urea composition); 3,843,799 toElofson et al (complex glucosylurea converted to ammonia in rumen); and4,044,156 to Diner et al (monoglucoxyl ureide). Ruminant feedsupplements which are formulated to be resistant to microbial breakdownin the rumen, but not resistant to substantial digestive breakdown inthe abomasum and intestines have been disclosed in U.S. Pat. Nos.:3,988,480 to Ames et al; 3,959,493 to Ballsrud et al; 4,001,390 toFildes; and 3,562,806 to Grant et al.

Rumen bacterial respiration modifiers act through an effect on thebacterial population ordinarily present in the animals' digestive systemand reduce the amount of bacterial products which are not absorbed bythe ruminant. Feed supplements for ruminants which influence the O-Rpotential of microfloral respiration in the rumen have been disclosed asfeed efficiency agents in U.S. Pat. No. 2,808,332 to Anderson et al. Thereduction of gaseous waste production in ruminates has been reported inU.S. Pat. No. 3,801,710 to Parish et al which discloses theadministration to ruminates of certain haloalkehyde sulfonates andphosphonates. U.S. Pat. No. 3,796,797 to Parish discloses theadministration to ruminants of a chloral molasses feed.

Other agents, such as the anticholinergics have also been used.

Most of these known growth promotants can have undesired side effects.The antibacterials and antiparasitics pose the problem that their usewill result in resistant strains of disease-causing bacteria. Hormonalagents can also produce unwanted side effects, and in some cases, suchagents have been shown to be carcinogenic. Sedatives and tranquilizerscan leave undesirable residues in the animal. The effectiveness ofanticholinergics is limited due to the undesirable side effectsmanifested when therapeutic doses are administered.

The present invention is directed to improved means for effecting feedefficiency in animals.

SUMMARY OF THE INVENTION

This invention relates to feed efficiency supplements, feed additivecompositions, a method for increasing the feeding efficiency of animals,and, in particular, a method for increasing the digestive absorption ofnutrients in an animal to increase said animal's feed efficiency andcomprises administering to an animal for assimilation by the animal amaterial which increases the dwell time of nutrient matter in thedigestive tract of said animal, the administration of said materialbeing for a period of time sufficient to effect an increase in thedigestion and absorption of said nutrients over and above that whichwould have been effected had the animal not assimilated said material.

Numerous benefits are achieved as a result of the use of the presentinvention. Efficient utilization of animal feed is realized without theadverse side effects that accompany the use of other growth promotants.Use of the present invention results not only in a reduction inconsumption of animal feed, but also in a reduction in waste generationowing to a more efficient digestive process.

Particularly preferred materials for use in the method of this inventioncomprise, for example, amidinoureas having antimotility properties,diphenoxylates and loperamide. The most preferred feed efficiency agentsare phenyl substituted amidinoureas having antimotility properties.

Another aspect of this invention relates to the shortening of the periodof growth from infancy to maturity in animals which produce food or toincreasing the production of development of animal products byadministering to the animals during its growth stages an effectiveamount of an antimotility agent.

Still another aspect of this invention relates to a method forincreasing the feed conversion ratio of a healthy feeding animal.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that compositions containing certain antimotilityagents are effective in lowering the unit amount of food consumed byfeeding animals per unit increase in animal production output, such as,body weight, milk production, egg production or fur production. Instandard laboratory screening tests, described more fully below, certainantimotility agents have been shown to be effective in increasing theresidence time of ingested food, and effecting a corresponding increasein the amount of digestible material actually digested and absorbed bythe test animals.

A particular class of compounds for use in practicing the invention areamidinoureas having antimotility properties. For example, theamidinoureas defined below are readily absorbed through the intestinalwall of mammals and fowl, and may be administered as compositionsformulated as tablets, capsules, powders or liquids suitable for eitherdirect oral administration or in combination with animal feed. Theantimotility agents used to increase feed efficiency can, if desired, beused in combination with other food additives such as growth promoters,compositions for providing electrolyte balance, agents for improvingtaste, smell, texture and the like, or with therapeutic agents such assulphonamides, sulphones, antibiotics, hormones, or with other suitableexcipients.

Compounds within the broad class of compounds which are useful in thepractice of the present invention are known in the art for the purposeof treating certain veterinary diseases, such as, scours, byadministering such compounds for limited periods of time at therapeuticdosages to counter the disease. In contrast, the present inventionrelates to the continuous feeding or the feeding on a regular basis of anon-therapeutic dosage of a feed efficiency agent irrespective of thepresence of any veterinary disease in the animal and for an extendedperiod of time. In normal use, this invention is practiced on a largenumber of healthy feeding animals, such as a herd of cattle or a flockof sheep, instead of selectively administering a therapeutic dose ofcompound to sickly members of the animal group.

Amidinoureas suitable for use in this invention and which can be used asthe principal active ingredient in the feed efficiency compositions ofthis invention are compounds of the formula: ##STR1## wherein one of R₁or R₅ is phenyl, phenyl in which one or more of the hydrogens issubstituted by halo, lower alkyl, halo lower alkyl, nitro, lower alkoxy,hydroxy, aryl lower alkoxy, acyloxy, cyano, halo lower alkoxy, or loweralkyl sulfonyl; aralkyl, heterocycle, or heterocycle having one or moreof the hydrogens replaced by lower alkyl, lower alkoxy, halo, halo loweralkyl, amino, nitro, hydroxy, cyano, carboxyl or lower alkyl sulfonyl;and the other of R₁ or R₅ is hydrogen, lower alkyl, lower alkoxy, loweralkenyl, cyclo lower alkenyl, cyclo lower alkyl, aralkyl, lower alkenyl,halo alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, cyano loweralkyl, amino lower alkyl, mono- or di-lower alkyl amino lower alkyl,carbamoyl lower alkyl, mono- or di-carbamoyl lower alkyl, lower alkoxycarbamoyl lower alkyl, aralkoxy carbamoyl lower alkyl, acyl lower alkyl,alkyl sulfonyl or aralkyl sulfonyl; R₂ and R₆ are each independentlyselected from the group consisting of hydrogen, lower alkyl, loweralkoxy, lower alkenyl, cyclo lower alkenyl, cyclo lower alkyl, aralkyl,lower alkynyl, halo alkyl, hydroxy lower alkyl, lower alkoxy loweralkyl, cyano lower alkyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, carbamoyl lower alkyl, mono- or di-carbamoyl loweralkyl, lower alkoxy carbamoyl lower alkyl, aralkoxy carbamoyl loweralkyl, acyl lower alkyl, alkyl sulfonyl or aralkyl sulfonyl; and when R₁is phenyl, phenyl substituted as above, aralkyl, heterocycle orheterocycle substituted as above, R₅ together with R₆ and the nitrogento which R₅ and R₆ are attached may form a 5 or 6 membered heterocyclicring which may include 0 to 2 additional hetero atoms which may beeither oxygen, nitrogen or sulfur; and when R₅ is phenyl, phenylsubstituted as above, aralkyl, heterocycle or heterocycle substituted asabove, either R₁ and R₂ together with the nitrogen to which they areattached, or R₁ and R₃ together with the nitrogen to which they areattached, may be a 5, 6, 7 or 8 membered heterocyclic ring which mayinclude 0 to 2 additional hetero atoms which may be either oxygen,nitrogen or sulfur; and R₃ and R₄ are each independently hydrogen, loweralkyl, lower alkoxy, lower alkenyl, lower alkynyl, cyclo lower alkyl oraralkyl; and their pharmaceutically acceptable acid addition salts.

It should be understood that whereas the structure of the amidinoureasare shown here in a particular configuration for purposes ofillustration, these compounds may exist in various enolized ortautomeric forms, particularly where one or R₃ and R₄ is hydrogen,shown, for example, by the following formula: ##STR2##

Certain of the compounds can also be obtained as hydrates or indifferent polymorphic forms. The structures used herein to designate theuseful compounds are intended to include the compound shown along withits alternative or transient states.

As employed above and throughout the disclosure, the following termsunless otherwise indicated shall be understood to have the followingmeanings:

"Alkyl" means a saturated aliphatic hydrocarbon which may be eitherstraight or branched chain. Lower alkyl groups are preferred.

"Lower alkyl" means an alkyl group as above, having about 1 to about 6carbon atoms. Suitable lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and isopentyl.

"Cycloalkyl" means an aliphatic monocyclic saturated carbocyclic group.Preferred groups have about 3 to about 6 carbon atoms, for example,cyclopropyl, cyclopentyl and cyclohexyl.

"Alkenyl" means an unsaturated aliphatic hydrocarbon containing one ormore double bonds and may be straight or branched chain. Lower alkenylare preferred.

"Lower alkenyl" means alkenyl of about 2 to about 6 carbon atoms, suchas, ethylene, propylene, butylene, isobutylene, etc.

"Alkynyl" means an unsaturated aliphatic hydrocarbon containing one ormore triple bonds. Lower alkynyl groups are preferred.

"Lower alkynyl" means alkynyl of about 2 to about 6 carbon atoms, suchas, propargyl, butynyl, pentynyl, etc.

"Aryl" is an aromatic radical group and includes phenyl and substitutedphenyl. Phenyl and substituted phenyl groups are preferred.

"Substituted phenyl" means a phenyl group in which one or more of thehydrogens has been replaced by the same or different substituentsincluding halo, carboxyl, lower alkyl, halo lower alkyl, nitro, amino,acylamino, hydroxy, lower alkoxy, aryl lower alkoxy, acyloxy, cyano,halo lower alkoxy or lower alkyl sulfonyl.

"Aralkyl" means an alkyl (preferably a lower alkyl) in which one or morehydrogens is substituted by aryl, for example, benzyl or phenethyl.

"Heterocycle" means a 5 to 8 membered ring having about 1 to about 3hetero atoms which may be nitrogen, oxygen or sulfur, including pyridyl,2-pyridyl or 3-pyridyl; pyrimidyl, pyrazolyl, imidazolyl, furyl,thienyl, oxazolyl, thiazolyl, piperidyl, piperazenyl, morpholinyl,thiomorpholinyl and diazipinyl. Pyridyl groups are preferred.

"Substituted heterocycle" means a heterocycle in which one or more ofthe hydrogens on the ring carbons have been replaced by substituents asgiven above with respect to substituted phenyl.

The terms "halo" and "halogen" include all four halogens; namely,fluorine, chlorine, bromine and iodine.

"Halo alkyl" and "halophenyl" include alkyl or phenyl groups having oneor more halo substituents which may be the same or different, such astrifluoromethyl, 1-chloro-2-bromoethyl, chlorophenyl,2-chloro-6-bromophenyl, etc.

The term "acyl" means a radical of the formula RCO, wherein R is anorganic radical, such as lower alkanoyl or aroyl. In lower alkanoyl, Ris alkyl, as in acetyl and propionyl, and in aroyl, R is aryl, as inbenzoyl.

The term "acyloxy" means an organic acid radical of the formula RCOOwherein R is an organic radical, such as acetoxy, propionoxy orbenzoyloxy.

The term "acylamino" means an organic amido group of the formula##STR3## where R is an organic alkyl group, preferably lower alkyl.

The term "lower alkanoyl" means the acid radical of a lower alkanoicacid, such as acetyl or propionyl.

Among the amidinoureas of Formula I, a particularly preferred group ofamidinoureas suitable for use in the composition and method of thisinvention are those in which the R₅ or R₁ substituent is a phenyl orsubstituted phenyl. A subclass of these compounds, of particularinterest, are where the phenyl substituents are in the 2 and 6 positions(i.e., ortho to the carbon attached to the urea nitrogen). Suchpreferred compounds can be represented by the formulae: ##STR4##

Particularly preferred compounds of Formulae I, II and III are thosewherein the R' and R" phenyl substituents are lower alkyl, halo loweralkyl, lower alkoxy or halo and at least one of the R₁, R₂, R₃, R₄ andR₅ is hydrogen. The preferred lower alkyl substituents are methyl,ethyl, propyl and isopropyl. The preferred halo substituents arechlorine and bromine. The preferred halo lower alkyl substituents arechloromethyl and trifluoromethyl.

A most preferred group of amidinoureas suitable for use in the practiceof this invention are the compounds of the formulae: ##STR5## whereinR₁, R₂, R₃ and R₄ are each hydrogen, lower alkyl, lower alkoxy orhydroxy; and R' and R" are each hydrogen, halo or lower alkyl.

The compounds of Formulae I to V can be used in the practice of thisinvention in the form of the base or as salts which may be prepared byreacting these compounds with pharmaceutically acceptable acids.Suitable acid addition salts are, for example, the salts derived fromthe following organic and inorganic acids: hydrochloric acid, nitricacid, sulfuric acid, phosphorous acid, orthophosphoric acid, etc.;aliphatic mono- and dicarboxylic acids such as acetic acid, propionicacid, succinic acid, formic acid, caprylic acid, maleic acid, oxalicacid, malonic acid, etc.; phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic carboxylic acids, and aliphatic and aromaticsulfonic acids such as methylbenzoic acid, phthalic acid,benzenesulfonic acid, phenylpropionate, tartaric acid, citric acid,lactic acid, glycollic acid, phenylacetic acid, phenylbutyric acid,methane sulfonic acid, etc.

Suitable amidinoureas for use as feed efficiency supplements are alsothose disclosed in the Arzneimittel Forschung, 28 (II), 1433-1480 (1978)and in U.S. Pat. Nos. 4,115,647; 4,088,785; 4,025,652; 4,115,564;4,060,633; 4,246,409; 4,058,557 and 4,147,804, the disclosures of whichare incorporated herein by reference.

The amidinoureas employed as principal active ingredients in thecompositions and methods of this invention are prepared by methods knownin the art, as disclosed in the incorporated references noted above.

Exemplary compounds prepared in accordance with such teachings forutilization in this invention are named below wherein the urea nitrogensare designed as positions 1 and 3:

1-(2,6-dimethylphenyl)-3-methylamidinourea

O-chlorophenylamidinourea

(2,3-dichlorophenylamidino)urea

(2,4-dichlorophenylamidino)urea

(2,5-dichlorophenylamidino)urea

1-(2',6'-dimethylphenyl)-3-(1',1',3',3'-tetramethylamidino)-urea

(3,4-dichlorophenylamidino)urea

(3,5-dichlorophenylamidino)urea

(2,6-dichlorophenylamidino)urea

m-chlorophenylamidinourea

p-chlorophenylamidinourea

3,4-difluorophenylamidinourea

m-bromophenylamidinourea

p-bromophenylamidinourea

3,4-dibromophenylamidinourea

3-chloro-4-bromophenylamidinourea

3-bromo-4-chlorophenylamidinourea

3-chloro-4-fluorophenylamidinourea

3-bromo-4-fluorophenylamidinourea

3-fluoro-4-chlorophenylamidinourea

2,6-dimethylphenylamidinourea

2,6-diethylphenylamidinourea

2-methyl-6-ethylphenylamidinourea

2-methyl-6-methoxyphenylamidinourea

2-methyl-6-ethoxyphenylamidinourea

2-ethyl-6-ethoxyphenylamidinourea

3,4-dimethoxyphenylamidinourea

3,4-dihydroxyphenylamidinourea

3,4,5-trimethoxyphenylamidinourea

3,4,5-trihydroxyphenylamidinourea

1-(2,6-dimethylphenylamidino)-3,3-(N-methyl-3'-azapentamethylene)urea

1-(2,6-dimethylphenylamidino)-3,3-(N-methyl-3'-azahexamethylene)urea

1-(2,6-dimethylphenylamidino)-3,3-(3'-oxapentamethylene)urea

1-(2,6-dimethylphenylamidino)-3,3-(2,'-thiatetramethylene)urea

1-(2,6-dimethylphenylamidino)-3,3-tetramethyleneurea

1-(p-fluorophenylamidino)-3,3-(α,α'-dimethylpentamethylene)urea

1-(2,6-dimethylphenylamidino)-3,3'-(α,α'-dimethylpentamethylene)urea

1-(2,6-dimethylphenylamidino)-3,3-(pentamethylene)urea

1-(2,6-dimethylphenylamidino)-3,3-(α-methylpentamethylene)urea

1-(N-methylamidino)-3-(2,6-dimethylphenyl)urea

1-(N-methylamidino)-3-(2,6-diethylphenyl)urea

1-amidino-3-(2-methyl-6-chlorophenyl)urea

1-amidino-3-(2-methyl-6-bromophenyl)urea

1-amidino-3-(2-methyl-6-methoxyphenyl)urea

1-amidino-3-(2,6-dimethylphenyl)urea

1-amidino-3-(2-methyl-6-ethylphenyl)urea

1-amidino-3-(2-ethyl-6-chlorophenyl)urea

1-amidino-3-(2,6-diethylphenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-chlorophenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-bromophenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-methoxyphenyl)urea

1-amidino-3-methyl-(2,6-dimethylphenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-ethylphenyl)urea

1-amidino-3-methyl-3-(2-ethyl-6-chloropyenyl)urea

1-amidino-3-methyl-3-(2-ethyl-6-bromophenyl)urea

1-amidino-3-methyl-3-(2-ethyl-6-methoxyphenyl)urea

1-amidino-3-methyl-3-(2,6-diethylphenyl)urea

1-amidino-3-(2-methyl-6-chlorophenyl)urea

1-amidino-3-(2-methyl-6-bromophenyl)urea

1-amidino-3-(2,6-dimethyl-4-hydroxyphenyl)urea

1-amidino-3-(2,6-dimethyl-3-hydroxyphenyl)urea

1-amidino-3-(2,6-dimethyl-3,4-dihydroxyphenyl)urea

1-amidino-3-(2,6-dimethyl-3,4,5-trihydroxyphenyl)urea

1-amidino-3-(2,6-dimethyl-4-methoxyphenyl)urea

1-amidino-3-(2,6-dimethyl-3-methoxyphenyl)urea

1-amidino-3-(2,6-diemthyl-3,4-dimethoxyphenyl)urea

1-amidino-3-(2,6-dimethyl-4-ethoxyphenyl)urea

1-amidino-3-(2,6-dimethyl-4-ethoxyphenyl)urea

1-amidino-3-(2,6-dimethyl-3,4-diethoxyphenyl)urea

1-(2,6-dimethyl-4-hydroxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-3-hydroxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-3,4-dihydroxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-4-methoxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-3-methoxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-3,4-dimethoxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-4-ethoxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-3-ethoxyphenyl)-3-methylamidinourea

1-(2,6-dimethyl-3,4-diethoxyphenyl)-3-methylamidinourea

1-amidino-3-(2,6-dimethylphenyl)urea

1-amidino-3-(2-methyl-6-ethylphenyl)urea

1-amidino-3-(2-ethyl-6-chlorophenyl)urea

1-amidino-3-(2-ethyl-6-bromophenyl)urea

1-amidino-3-(2-ethyl-6-methoxyphenyl)urea

1-amidino-3-(2,6-diethylphenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-chlorophenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-bromophenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-methoxyphenyl)urea

1-amidino-3-methyl-3-(2,6-dimethylphenyl)urea

1-amidino-3-methyl-3-(2-methyl-6-ethylphenyl)urea

1-amidino-3-methyl-3-(2-ethyl-6-chlorophenyl)urea

1-amidino-3-methyl-3-(2-ethyl-6-bromophenyl)urea

1-amidino-3-methyl-3-(2-ethyl-6-methoxyphenyl)urea

1-amidino-3-methyl-3-(2,6-diethylphenyl)urea

1-(2,6-dichlorophenylamidino)-3-n-propylurea

1-(2,6-dimethylphenyl)-3-(isopropylamidino)urea

1-(4-bromo-3-chloro-6-methylphenyl)-3-methylamidinourea

1-(2-bromo-6-methylphenyl)-3-methylamidinourea

1-(2,6-dimethylphenyl)-3-(N-methyl-N'-propylamidino)urea

The amidinoureas of Formulae I to V and their pharmaceuticallyacceptable salts are useful as feed efficiency agents. The antimotilityactivity and enhanced food nutrient digestion and absorption activity ofthese amidinoureas have been demonstrated for representative compoundswithin the class of compounds defined by Formulae I to V inclusive.

Among the tests which demonstrate the usefulness of those compounds inaccordance with this invention are the following:

Gastric Emptying

The gastric emptying test is performed essentially as described byBrodie. Male Sprague-Dawley rats (groups of five) are dosed orally withthe test compounds 30 minutes before the oral administration of 30Amerlite pellets (Rohm & Haas Amberlite 1RA-93, 1 mm diameter) suspendedin 1 ml distilled water. The animals are killed with pentobarbital fourhours after the pellets are given, the stomachs are removed and thenumber of pellets remaining in the stomachs are counted. The controlgroup is compared to the drug treated group using the following formula:%retention=[(mean drug-treated)-(mean control)]/[30-(mean control)]

                  TABLE I                                                         ______________________________________                                         ##STR6##                                                                                                       Dose                                        R'     R"     Rm       R.sub.6                                                                            R.sub.5                                                                             mg/kg % Inhib.                              ______________________________________                                        CH.sub.3                                                                             H      H        H    H     10    54                                    H      H      4NO.sub.2                                                                              H    H     10    59                                    Cl     H      4-Cl     H    H     10    85                                    H      H      3-Cl,    H    H     10    74                                                  4-Cl                                                            CH.sub.3                                                                             H      4-Cl     H    H     10    28                                    Cl     H      4-CH.sub.3                                                                             H    H     10    40                                    Cl     Cl     4Br      H    H     40    54                                    CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3                                                                             H    H     10    45                                    Cl     F      H        H    H     0.25  60                                    Cl     Cl     H        H    H     0.125 54                                    Cl     CH.sub.3                                                                             H        H    H     0.25  43                                    OCH.sub.3                                                                            CH.sub.3                                                                             H        H    H     0.5   70                                    CH.sub.3                                                                             CH.sub.3                                                                             H        H    H     0.25  55                                    ET     CH.sub.3                                                                             H        H    H     0.5   30                                    ET     ET     H        H    H     2.5   83                                    CH.sub.3                                                                             CH.sub.3                                                                             H        CH.sub.3                                                                           H     2     55                                    ______________________________________                                    

Charcoal Motility

A charcoal suspension (10 ml/kg of a 10% suspension of activatedcharcoal, U.S.P. in 0.5% methylcellulose) is given orally either togroups of 10 Swiss-Webster male mice (18-22 g, Taconic Farms) or groupsof 5 Sprague-Dawley male rats (120-140 g, Charles River Breeding Labs.,Inc.) 30 minutes after an oral dose of drug or vehicle. The animals aresacrificed 30 minutes after receiving the charcoal and the intestinesare carefully removed without stretching and placed lengthwise on moistpaper. The length of the intestine (pyloric sphincter to caecum) and thedistance traveled by the charcoal as a fraction of that length areevaluated for each animal and group means are compared and expressed aspercentage inhibition. ##EQU1## For estimation of the duration ofinhibition, the interval between dosing with drug and the administrationof charcoal is varied from 30 minutes to 6 hours.

                  TABLE II                                                        ______________________________________                                         ##STR7##                                                                                                       Dose                                        R'     R"     Rm       R.sub.6                                                                            R.sub.5                                                                             mg/kg % Inhib.                              ______________________________________                                        CH.sub.3                                                                             H      H        H    CH.sub.3                                                                            4     11                                    H      H      4-NH.sub.2                                                                             H    ET    4     20                                    CH.sub.3                                                                             CH.sub.3                                                                             3Br      H    CH.sub.3                                                                            4     22                                    CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3                                                                             H    n-Pr  4     15                                    Br     Br     H        H    H     4     91                                    Br     CH.sub.3                                                                             H        H    H     4     89                                    CH.sub.3                                                                             NO.sub.2                                                                             H        H    H     4     82                                    Cl     CH.sub.3                                                                             H        CH.sub.3                                                                           H     4     82                                    CH.sub.3                                                                             CH.sub.3                                                                             H        n-Bu H     4     72                                    ET     ET     H        CH.sub.3                                                                           H     4     12                                    ______________________________________                                    

Studies on poultry conducted under strict laboratory conditions, thatis, in a disease and parasite-free environment, indicate that theadministration of the feed efficiency agents, such as, the amidinoureasdefined in Formulae I-V, and, in particular,1-(2,6-dimethylphenyl)-3-methylamidinourea, results in an increase infeed conversion ratio, and weight gain of the treated animal relative tothat of the control animals. The feed conversion ratio, defined as the##EQU2## is observed as being improved in the treated animals by afactor of up to about 10%, and averaged over a five week period of up toabout 5%.

In addition to the amidinoureas illustrated above as suitable feedefficiency agents for use in accordance with the method of thisinvention, other compounds possessing antimotility activity and lackinggrowth retardant properties such as diphenoxylates and loperamide canalso be used. Moreover, any one or more of these agents, including theamidinoureas, can be used in combination, It should be understood thatcompounds which have antimotility activity but which possess additionalproperties which act to retard digestion and absorption of feednutrients are not encompassed within this invention.

The feed efficiency compounds can be utilized in accordance with thisinvention to achieve increased feed efficiency in food-producing animalsby simply administering an effective amount generally less than thetherapeutic dose where the compound also has therapeutic effects.Ordinarily, a daily dose between about 1 ppm to 20 ppm in the dailyration is sufficient to substantially increase the food retention andproduce higher feed efficiency than is achieved by the animal withoutthe administration of the feed efficiency agent.

In a preferred embodiment, the amidinoureas of Formulae I-V are utilizedin dosage amounts between about 0.005 and about 0.5 mg/kg, and mostpreferably about 0.01 and about 0.1 mg/kg daily, administered in theanimals' feed intake. A particularly preferred compound is1-(2,6-dimethylphenyl)-3-methylamidinourea administered in an amountbetween about 0.01 and about 0.1 mg/kg. The amidinoureas are suitableutilized as their edible acid addition salts, preferably thehydrochloride salt.

The compounds used as feed efficiency agents in accordance with thisinvention can be administered along with the animals' normal dietaryintake or compounded with other food additives or food supplements. Forexample, where protein supplements are used, such as in feeding cattleand sheep, the feed efficiency agents can be incorporated into theprotein supplement. The feed efficiency agents are preferablyadministered during the normal growth stage of the animals. The feedefficiency agents can also be fed directly to the animals with orwithout suitable diluents and other edible excipients, or they can beprepared in the form of powders, pellets and the like for distributionin the feed materials such as silage, oats, barley, bran and the like.They can also be combined with other feed supplements such as bonemeal,salt, trace minerals, vitamins, antibiotics, growth hormones, etc. Theamount to be included in the animals' feed materials or in feedsupplements can be portioned in accordance with the animals' feed rationsuch that the effective amount of the feed efficiency agent on a dailyadministration basis is incorporated into the animals' daily feedration.

By way of example, calves, in their early to mid growth stage, will showbetter food utilization when about 0.5 to 10 milligrams, preferably 1 to5 milligrams and more preferably about 1 to 2.5 milligrams of anantimotility feed efficiency agent, particularly an amidinourea of thetype described in Formulae I to V, is uniformly distributed throughoutone kilogram of the feed materials. The feed efficiency agents can alsobe administered via other means, either directly or in combination withliquid or solid feed supplements such as feed blocks, salt blocks, andthe like.

A preferred means of making the feed efficiency agents of the presentinvention available to feeding animals is by the uniform distribution ofthe feed efficiency agent throughout the animal feed. This distributionis facilitated by the preparation of a feed additive premix containing ahigher concentration of feed supplement than the animal feed per se. Thepremix, which may be added to the feed in a ratio of 1 lb premix to 1ton feed, comprises from about 2 to about 4 g/kg of feed efficiencyagent and an edible carrier, preferably animal feed. The premix may alsocontain additional feed supplements as discussed above, such as,antibacterial agents, antiparasitics and tranquilizers.

The compositions and method of this invention are useful for improvingthe feed efficiency of all animals grown for commercial food productionpurposes, including those animals which are grown for meat productionsuch as cattle, sheep, hogs, rabbits, chickens, ducks, geese, turkeys,pheasants and the like, as well as those animals which are grown forproduction of other food or useful animal products such as diaryproducts, eggs, wool, fur and the like. Use of the compositions andmethod of this invention will shorten the growth period when fed toanimals during their growing stages thereby reducing the time from birthto slaughter for animals grown for products such as meat, furs and thelike. When used with mature animals, the compositions and method of thisinvention reduce the animal feed requirement to maintain the animal atfull productivity, including work animals such as horses. In all cases,the use of the compositions and the method of this invention provide agreater output of animal products relative to the amount of animal feedconsumed than could be achieved by maintaining the animal at the samefeed regimen without such agents for improving feed efficiency.

It should be understood that the examples given herein are by way ofillustration only and are not to be construed as limiting the invention,which contemplates the administration of any compound possessingantimotility properties and enhanced feed nutrient digestive andabsorptive activity to foodproducing animals which provide meat, milk,etc., particularly livestock and poultry, to obtain higher foodproduction per unit of animal feed material consumed.

I claim:
 1. In a process in which the feed efficiency of an animalpopulation of poultry is increased the improvement comprisingadministering to said animal population, including in said populationhealthy animals, about 0.01 to about 0.1 mg/kg of animal body weight ofa material which increases the dwell time of nutrient matter in thedigestive tract of said animal, the administration of said materialbeing for a period of time sufficient to effect an increase in thedigestion and absorption of said nutrients over and above that whichwould have been effected had the animal not assimilated said materialwherein said material is an amidinourea of the formula ##STR8## whereinR₁, R₂, R₃ and R₄ are hydrogen, halo lower alkyl, lower alkoxy, or loweralkyl; R₆ is hydrogen or lower alkyl; R' and R" are hydrogen, loweralkyl, lower alkoxy, halo or halo lower alkyl; R is hydrogen, loweralkyl, halo, lower alkoxy, nitro, amino or halo lower alkyl and, n is0-3; and, the edible salts thereof.
 2. A process according to claim 1including administering to said animal population one or more additivesselected from the group consisting of antibacterials, antibiotics andantiparasitics.
 3. A process according to claim 1 wherein said materialis administered to said population in a non-therapeutic dosage amount.4. A process according to claim 1 including administering to said animalpopulation a non-therapeutic amount of said material and one or moreadditives selected from the group consisting of antibacterials,antibiotics and antiparasitics.
 5. A method according to claim 1 whereinsaid material is an amidinourea of the formula: ##STR9## wherein R₁, R₂,R₃ and R₄ are hydrogen, lower alkyl, lower alkoxy or hydroxy; R' and R"are hydrogen, halo or lower alkyl; and the edible salts thereof.
 6. Amethod according to claim 5 wherein said amidinourea is1-(2,6-dimethylphenyl)-3-methylamidinourea or an edible salt thereof ina dosage amount sufficient to increase the dwell time in the digestivetract of an animal feeding thereon.